Anti-tumor activity of a novel HS-mimetic-vascular endothelial growth factor binding small molecule

Basappa, Kazuyuki Sugahara, Kuntebommanahalli N. Thimmaiah, Hemant K. Bid, Peter J Houghton, Kanchugarakoppal S. Rangappa

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The angiogenic process is controlled by variety of factors of which the vascular endothelial growth factor (VEGF) pathway plays a major role. A series of heparan sulfate mimetic small molecules targeting VEGF/VEGFR pathway has been synthesized. Among them, compound 8 (2-butyl-5-chloro-3-(4-nitro-benzyl)-3H-imidazole-4-carbaldehyde) was identified as a significant binding molecule for the heparin-binding domain of VEGF, determined by high-throughput-surface plasmon resonance assay. The data predicted strong binding of compound 8 with VEGF which may prevent the binding of VEGF to its receptor. We compared the structure of compound 8 with heparan sulfate (HS), which have in common the functional ionic groups such as sulfate, nitro and carbaldehyde that can be located in similar positions of the disaccharide structure of HS. Molecular docking studies predicted that compound 8 binds at the heparin binding domain of VEGF through strong hydrogen bonding with Lys-30 and Gln-20 amino acid residues, and consistent with the prediction, compound 8 inhibited binding of VEGF to immobilized heparin. In vitro studies showed that compound 8 inhibits the VEGF-induced proliferation migration and tube formation of mouse vascular endothelial cells, and finally the invasion of a murine osteosarcoma cell line (LM8G7) which secrets high levels of VEGF. In vivo, these effects produce significant decrease of tumor burden in an experimental model of liver metastasis. Collectively, these data indicate that compound 8 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of endothelial cell migration and angiogenesis mediated by VEGF. In conclusion, compound 8 may normalize the tumor vasculature and microenvironment in tumors probably by inhibiting the binding of VEGF to its receptor.

Original languageEnglish (US)
Article numbere39444
JournalPLoS One
Volume7
Issue number8
DOIs
StatePublished - Aug 15 2012
Externally publishedYes

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Heparitin Sulfate
vascular endothelial growth factors
Vascular Endothelial Growth Factor A
Tumors
Molecules
neoplasms
Neoplasms
heparin
Heparin
Endothelial cells
endothelial cells
heparan sulfate
Endothelial Cells
surface plasmon resonance
receptors
imidazoles
hydrogen bonding
Tumor Microenvironment
osteosarcoma
Surface Plasmon Resonance

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Anti-tumor activity of a novel HS-mimetic-vascular endothelial growth factor binding small molecule. / Basappa; Sugahara, Kazuyuki; Thimmaiah, Kuntebommanahalli N.; Bid, Hemant K.; Houghton, Peter J; Rangappa, Kanchugarakoppal S.

In: PLoS One, Vol. 7, No. 8, e39444, 15.08.2012.

Research output: Contribution to journalArticle

Basappa ; Sugahara, Kazuyuki ; Thimmaiah, Kuntebommanahalli N. ; Bid, Hemant K. ; Houghton, Peter J ; Rangappa, Kanchugarakoppal S. / Anti-tumor activity of a novel HS-mimetic-vascular endothelial growth factor binding small molecule. In: PLoS One. 2012 ; Vol. 7, No. 8.
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